[New options for the pharmacotherapy of Alzheimer's disease after the registration of memantine?].
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Alzheimer Disease↗
Biomedical subjects
R Ihl
Publications and source records attributed to R Ihl.
The impact of drugs against dementia on cognition in aging and mild cognitive impairment.
OBJECTIVE: To define the actual knowledge of the impact of drugs for the treatment of dementia on the improvement of cognition in aging and mild cognitive impairment. METHOD: We conducted a Medline search for studies with the parameters drug and cognition. Only drugs that had demonstrated cognition improvements in dementia according to actual methodological standards were included. Drugs had to be approved in at least one American or European nation. RESULTS: Donepezil, galantamine, Ginkgo biloba EGb 761 (definition see editorial), memantine and rivastigmine fulfilled these criteria. There were no systematic investigations on the effects of these drugs on cognition in healthy adults or patients with mild cognitive impairment (MCI). Regarding Ginkgo biloba, two studies on MCI patients could be identified. In healthy adults, we could only include one study investigating donepezil and seven investigating Ginkgo biloba EGb 761. According to the findings, donepezil significantly increased the percentage of REM sleep and REM density, whereas REM latency was reduced. This was interpreted as a sign of improved cognition. Ginkgo biloba EGb 761 improved cognition in healthy controls according to Delayed Free Recall and Delayed Recognition of the WAIS-III and the Color Naming of the Stroop Test as well as in MCI in Digit Copying, Dual Coding Task and speed of response on a computerized version of a classification task. The highest effects were observed after 6 weeks of treatment with 180 mg/d. CONCLUSIONS: Due to the lack of standard procedures for investigating cognition improvement in healthy aging, results have to be interpreted cautiously. In healthy adults as well as in individuals categorized as having MCI, Ginkgo biloba EGb 761 improved cognition in some but not all neuropsychological tests. The single positive result with donepezil raises hope that other drugs may also contribute to cognitive improvement, even in healthy adults. However, the data do not allow any conclusions regarding an improvement following a specific "neuropsychological cluster." Studies on prevention have not been completed so far.
Adult↗
[Dementing disorders. What benefits do the new anti-dementia drugs have?].
A critical analysis of the latest studies and meta-analyses dealing with antidementia agents, show that the efficacy of donepezil, galantamine, ginkgo biloba EGb 761, memantine, rivastigmine and tacrine in Alzheimer's disease is adequately confirmed. With the exception of tacrine, none of these substances are commonly associated with severe side effects. In the case of vascular dementia, the efficacy of ginkgo biloba EGb 761 and memantine has been demonstrated. Studies on the effectiveness of the cholinesterase inhibitors for this indication have been initiated. Antidementia agents can delay progression of the disease by about 6 to 12 months. Further studies are needed to confirm evidence of a prophylactic effect and a synergistic action of combinations.
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EEG-correlates of facial affect recognition and categorisation of blurred faces in schizophrenic patients and healthy volunteers.
The ability to recognise emotional expressions of faces and the ability to categorise blurred and non-blurred faces and complex objects was tested in 16 schizophrenic in-patients and 16 healthy volunteers. EEGs were recorded during performance of the tasks and event-related potentials were compared between groups. Patients performed worse than healthy volunteers in recognition of facial affect but not in categorisation of blurred faces. Furthermore, within a 180-250ms latency range patients showed reduced amplitudes during affect recognition compared with controls but not during categorisation of blurred faces. Amplitudes recorded at frontal electrode sites were associated with performance in facial affect recognition. These results provide a first clue to the neurophysiological basis of the widely reported facial affect recognition deficit in schizophrenic patients.
Adult↗
Electrophysiological correlates of emotional and structural face processing in humans.
In order to study brain potentials related to decoding of facial expressions of emotions and those, related to basic perception of faces 16 right-handed subjects performed tasks on facial emotion recognition and perception of blurred faces and objects. Electroencephalograph (EEG) recordings during performance of the tasks revealed similar event-related potentials during the presentation of faces at 120 and 170 ms after stimulus onset in both of the tasks but significant differences in amplitudes between 180 and 300 ms. Whereas faces in the emotion recognition task produced high amplitudes in that latency range, potentials in response to faces in the blurred object condition were virtually absent. These data point to the assumption that decoding of facial expressions starts early in the brain and might be processed separately from basic stages of face perception.
Adult↗
[Development and validation of a test for early diagnosis of dementia with differentiation from depression (TFDD)].
Psychometric tests used for the early detection of dementia often are seen as too difficult or too complex. Classical neuropsychologic tests were not developed for this purpose. Sensitivity and specificity to discriminate "healthy" vs. "ill" are low. For measuring both dementive and depressive symptoms, so far no test has been published. The objective of this study was to develop a sensitive and specific test for dementia that is easy to administer and to evaluate. Moreover, it should discriminate dementia from depressive pseudodementia. With respect to former studies, items were selected that recognized patients in the beginning of the disease. Additionally, depressive symptoms were rated. With the items for dementia, 88 patients with dementia of the Alzheimer type, 52 patients with depressive disorder and 37 healthy elderly controls were investigated. In this group of already diagnosed patients, the test reached a sensitivity and specificity of 100 percent (healthy elderly controls vs. patients with Alzheimer's disease: n = 125, U = 0, p < 0.001; patients with depressive disorder vs. patients with Alzheimer's disease: n = 140, U = 0, p < 0.001; healthy elderly controls vs. patients with depressive disorder: n = 89, U = 485.5, p < 0.001). For the dementia items, the inter-rater-reliability was rs = 0.996 (p < 0.001, n = 18), for the depression items it was rs = 0.753 (n = 18, p < 0.001). The test-retest-reliability was rs = 0.868 (p < 0.001, n = 35) for the dementia items and rs = 0.7 (n = 8, p < 0.05) for the depression items. These validation data will make the test useful for practitioners. Its ability to discriminate patients suffering from dementia of the Alzheimer type from healthy controls is comparable to tests consuming more time.
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A comparison of ADAS and EEG in the discrimination of patients with dementia of the Alzheimer type from healthy controls.
Neuropsychometric tests (for instance the Alzheimer's Disease Assessment Scale, ADAS) and the EEG are often used in the diagnostic procedure of dementia. The validity of the instruments is only poorly investigated. The study aimed to investigate the accuracy of the discrimination between healthy controls and patients with dementia of the Alzheimer type (DAT) by ADAS and EEG. Thirty-six patients with DAT and 44 healthy controls were included. In a discriminant analysis of the 21 ADAS items and 18 EEG parameters (6 frequency bands, 12 topographic parameters), 6 ADAS items turned out to discriminate both groups with 100% sensitivity and specificity (remembering instructions, depression, following commands, pacing, restlessness and word finding difficulties). Regarding EEG parameters, 4 (topography of beta- and delta-activity and amplitude of delta-activity) led to a sensitivity and specificity of over 90%. Thus, both methods demonstrated an excellent discrimination between healthy controls and DAT. The slightly higher discrimination with the ADAS may depend on its closer relation to clinical symptoms. However, the EEG measuring functional activity reached nearly the same result. Both methods provide complementary information. A combination of both methods in the diagnostic procedure to detect dementia is recommended.
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Neuropsychometric tests in cross sectional and longitudinal studies - a regression analysis of ADAS - cog, SKT and MMSE.
INTRODUCTION: In clinical and drug studies, different neuropsychometric tests are used. So far, no empirical data have been published to compare studies using different tests. The purpose of this study was to calculate a regression formula allowing a comparison of cross-sectional and longitudinal data from three neuropsychometric tests that are frequently used in drug studies (Alzheimer's Disease Assessment Scale, ADAS-cog; Syndrom Kurz Test, SKT; Mini Mental State Examination, MMSE). METHOD: 177 patients with dementia according to ICD10 criteria were studied for the cross sectional and 61 for the longitudinal analysis. Correlations and linear regressions were calculated between tests. Significance was proven with ANOVA and t-tests using the SPSS statistical package. RESULTS: Significant Spearman correlations and slopes in the regression occurred in the cross sectional analysis (ADAS-cog-SKT r(s) = 0.77, slope = 0.45, SKT-ADAS-cog slope = 1.3, r2 = 0.59; ADAS-cog-MMSE r2 = 0.76, slope = -0.42, MMSE-ADAS-cog slope = -1.5, r2 = 0.64; MMSE-SKT r(s) = -0.79, slope = -0.87, SKT-MMSE slope = -0.71, r2 = 0.62; p<0.001 after Bonferroni correction; N = 177) and in the longitudinal analysis (SKT-ADAS-cog, r(s) = 0.48, slope = 0.69, ADAS-cog-SKT slope = 0.69, p<0.001, r2 = 0.32, MMSE-SKT, r(s) = 0.44, slope = -0.41, SKT-MMSE, slope = -0.55, p<0.001, r2 = 0.21). CONCLUSIONS: The results allow calculation of ADAS-scores when SKT scores are given, and vice versa. In longitudinal studies or in the course of the disease, scores assessed with the ADAS-cog and the SKT may now be statistically compared. In all comparisons, bottom and ceiling effects of the tests have to be taken into account.
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[Nootropic drug evaluation for general practice].
Treatment with "nootropic drugs" of patients suffering from dementia is often described as arbitrary. To define the potential usefulness of nootropic drugs, effects and side effects, economic aspects in comparison to other treatment approaches were studied. A summary of literature published concerning these criteria underlines the efficacy of nootropics in improving the symptoms at the beginning and in postponing the progress of the disease. The majority of substances does not lead to severe side effects. There are not enough studies comparing the effects of the substances or on prophylactic effects. Delayed admission to care units leads to a positive cost effect of nootropics. Thus, also for economic reasons it seems advisable to treat patients with nootropics. Better effects are gained when nootropic treatment is combined with training and changing of the structure of the environment. A proposal for a rational treatment with nootropics is derived from the data.
Alzheimer Disease↗
Alzheimer's Disease Assessment Scale: reliability and validity in a multicenter clinical trial.
Psychometric characteristics of the Alzheimer's Disease Assessment Scale (ADAS) were examined on the basis of data from 440 patients with dementia of the Alzheimer type that were collected before treatment in a multicenter clinical drug trial. Coefficients of internal consistency of above .80 for the cognitive (ADAS-Cog) and the noncognitive section (ADAS-Noncog) indicated a high degree of homogeneity of item contents within the two assessment domains. Test-retest reliability was estimated to be .93, .98, and .96 for ADAS-Cog, ADAS-Noncog, and the total score (ADAS-Total), respectively. Reliably detectable individual changes, which were derived from the reliability estimates, were 7, 3, and 8 points for ADAS-Cog, ADAS-Noncog, and ADAS-Total, in that order. Factor analysis and correlations with MMSE, SKT, and NOSGER scores support the validity of the ADAS-Cog and ADAS-Noncog scores with regard to the cognitive and the noncognitive assessment domains. The ADAS summary scores, almost all of the cognitive items, and some of the noncognitive items discriminated significantly between stages of severity of dementia, as classified independently by MMSE and SKT scores.
Adult↗
The AMDP modules I-IV: recommendations for a standardized acquisition of EEG data in psychiatry. Association for Methodology and Documentation in Psychiatry.
During the last few years, the working group 'Psychophysiology' of the Association for Methodology and Documentation in Psychiatry (AMDP) discussed the possibility of the establishment of defined EEG modules in psychiatry. It was the aim to create a common data pool in order to be able to have access to larger data sets. The installation of such a common data pool was regarded as an important prerequisite for a future diagnostic application of EEG and EP data in clinical practice. The most relevant arguments are: From a statistical point of view, multivariate investigations can be improved when relatively large data sets are available. Subgrouping of patients is facilitated. Different centers have access to different populations of patients. Furthermore, compliance with the recommendations contributes to a reduction in misunderstanding and false interpretation of other investigators' results. The working group 'Psychophysiology' of the AMDP now recommends EEG modules to be registered in psychiatry. The recommendations are based on investigations using these modules in clinical research and practice as well as several years of discussion within the working group. Four AMDP modules (I-IV) are presented: MI: resting EEG (closed eyes), MII: resting EEG (eyes open), MIII: EEG during videotracking, and MIV: EEG during choice reaction time. Recommendations for additional modules are planned in the near future: MV: EEG during geometry test, MVI: EEG during labyrinth test, and MVII: amplitude stimulus intensity function. MIII-MVI is paralleled by an EEG recording so that psychomotor performance can be measured and EEG data under different activation conditions are available. Compliance with the recommendations guarantees the possibility of access to the common data pool. Computer software is available in Berlin.
Electroencephalography↗
Topography of the maximum of the amplitude of EEG frequency bands in dementia of the Alzheimer type.
The localization of the maxima of activity of 36 patients with dementia of the Alzheimer type and 36 age-matched controls was calculated after Fourier transformation of EEG data in six frequency bands (4 Hz steps between 1 and 24 Hz). Patients were divided into three groups of severity (BCRS mean < 3,9, 4.0-4.9, and > 4.9). Significant differences were found in the beta frequency band. In the distribution of the maxima of the activity, the maxima of patients were located more frontally than the maxima of controls. The alterations were staged dependent. The beta activity in EEG is said to be correlated with cognitive processes; the correlation between cognitive decline and decreasing beta activity in dementia of the Alzheimer type might support this assumption. Differences in the location of the maxima between patients and controls might allow for differentiation between both groups.
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Selective binding of soluble Abeta1-40 and Abeta1-42 to a subset of senile plaques.
Alzheimer's disease is characterized by the progressive accumulation of amyloid-beta protein (Abeta) in senile plaques and cerebral amyloid angiopathy. It is not known whether the plaque growth is a continuous and homogeneous process or whether some plaques have a more rapid evolution. As plaques grow by the deposition of Abeta, we used an in situ binding technique to analyze the deposition of fluorescein-conjugated and biotinylated Abeta1 40 and Abeta1-42 in cryosections of brains from Alzheimer's disease patients. Only a subset of senile plaques but all cerebrovascular Abeta deposits were labeled by both Abeta1-40 and Abeta1-42. Striking differences in binding were observed among adjacent plaques. Quantitative analysis showed that on average 60% of all plaques were labeled with Abeta1-42 and 31% of all plaques were labeled with Abeta1-40 (n=7; P<0.001). Confocal laser scanning microscopy of double-labeled sections revealed that the newly deposited Abeta was only partially co-localized to pre-existing Abeta and apolipoprotein E and was not co-localized to heparan sulfate proteoglycan. Abeta binding was preserved after glycolytic pretreatment with periodic acid. Our results suggest that at a given time point only a subset of active senile plaques accumulate A(beta) and that plaque growth may be conditioned by the presence of other distinct plaque components different from Abeta, apolipoprotein E or heparan sulfate proteoglycan.
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Correlation between cognitive brain function and electrical brain activity in dementia of Alzheimer type.
Psychometric tests which assess cognitive brain function in dementia disorders are partly prone to artifacts, e.g., the experience of the investigator and the cooperation of the patient influences the results. An objective way to assess the degree of cognitive disturbance could be to measure neuronal activity represented by the electrical brain activity. The aim of the present study was to investigate how well cognitive function in dementia assessed by psychometric tests correlates with electrical brain activity (EEG). Multichannel EEG data was reduced into 3-D intracerebral equivalent dipole EEG generators allowing a more convenient statistical data management and valid physiological data interpretation. 35 patients suffering from dementia of Alzheimer type were investigated. An increase of dipole strength in the slow frequency bands, a more anterior equivalent dipole of alpha- and beta-activity, and a slowing of the EEG with increasing cognitive deterioration could be demonstrated. The results support the hypothesis that the amount of disturbance of cognitive function in dementia can be assessed by measuring the electrical activity of the brain.
Adult↗
Event-related potentials and psychopharmacology. Cholinergic modulation of P300.
The event-related potential P300 probably reflects the encoding of information into short-term memory. Anatomical structures of the limbic system are involved in this process. Since the same structures are involved in the generation of the event-related potential P300, P300 is thus well suited to assess pharmacological influence on memory functions and cognitive processes, for example, by changing the availability of neurotransmitters like acetylcholine at their respective receptors.
Adult↗
[Dementia and disorders of the thyroid gland].
Cognitive deficits pretending dementia can be caused by thyroid dysfunction. The literature addressing pathophysiology and therapy of thyroid dysfunction is reviewed. A shorter duration and less severe course of thyroid dysfunction seem to indicate a better response to therapy. There are not studies on the latency between therapy and response. It is recommended to measure at least TSH in the differential diagnosis of dementive syndromes. Degenerative dementia can occur in coincidence with thyroid dysfunction. Therapy would improve at least symptoms caused by the thyroid dysfunction.
Dementia↗
Age-related changes of spontaneous EEG described by equivalent dipoles.
One of the most commonly used methods for quantification of an EEG is Fast Fourier Transformation (FFT), which suffers from some serious disadvantages, for example: FFT-power data are highly dependent on the choice of reference and thus the topographical distribution of FFT-power data varies according to the used reference. Novel methods which partly resolve this problem have been developed. These methods provide unambiguous data in the frequency domain with regard to reference. In comparison to conventional FFT-power data this approach allows to a higher degree to draw topographical valid conclusions regarding brain function. The aim of the present study on brain electrical activity, using the method of FFT approximation, was to investigate age-related alterations of brain function in carefully screened healthy subjects. The major finding was that, except for a more superficially located beta-activity of higher strength with increasing, age no age-related changes in electrical brain activity were observed.
Adult↗
Dementia of the Alzheimer type: effects on the spontaneous EEG described by dipole sources.
The present study on brain electrical activity in healthy subjects (n = 35) and patients suffering from dementia of the Alzheimer type (DAT; n = 35) used Fast Fourier Transformation-dipole approximation to quantify differences between the two groups. DAT patients showed a shift of alpha and beta activity toward frontal brain regions. The amount of this shift correlated with the degree of dementia. The relative distribution of magnitude of activity between the frequency bands differed between DAT patients and control subjects. DAT patients had higher magnitudes in the slow frequency range, correlating with the severity of dementia, and lower ones in the alpha and beta range compared with findings in age-matched control subjects.
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